ROLE OF NITRIC-OXIDE, CYCLIC-NUCLEOTIDES, AND THE ACTIVATION OF ATP-SENSITIVE K-INDUCED PIAL ARTERY DILATION( CHANNELS IN THE CONTRIBUTION OF ADENOSINE TO HYPOXIA)

Previously, it had been observed that nitric oxide (NO) contributes to hypoxia-induced pial artery dilation in the newborn pig. Additionally , it was also noted that activation of ATP-sensitive K+ channels (K-AT P) contribute to cGMP-mediated as well as to hypoxia-induced pial dila tion. Although somewhat controversial, adenosine is also thought to co ntribute to hypoxic cerebrovasodilation. The present study was designe d to investigate the role of NO, cyclic nucleotides, and activation of K-ATP channels in the elicitation of adenosine's vascular response an d relate these mechanisms to the contribution of adenosine to hypoxia- induced pial artery dilation. The closed cranial window technique was used to measure pial diameter in newborn pigs. Hypoxia-induced artery dilation was attenuated during moderate (PaO2 approximate to 35 mm Hg) and severe hypoxia (PaO2 approximate to 25 mm Hg) by the adenosine re ceptor antagonist 8-phenyltheophylline (8-PT) (10(-5) M) (26 +/- 2 vs. 19 +/- 2 and 34 +/- 2 vs. 22 +/- 2% for moderate and severe hypoxia i n the absence vs. presence of 8-PT, respectively). This concentration of 8-PT blocked pial dilation in response to adenosine (8 +/- 2, 16 +/ - 2, and 23 +/- 2 vs. 2 +/- 2, 4 +/- 2, and 6 +/- 2% for 10(-8), 10(-6 ), and 10(-4) M adenosine before and after 8-PT, respectively). Simila r data were also obtained using adenosine deaminase as a probe for the role of adenosine in hypoxic pial dilation. Adenosine-induced dilatio n was associated with increased CSF cGMP concentration (390 +/- 11 and 811 +/- 119 fmol/ml for control and 10(-4) M adenosine, respectively) . The NO synthase inhibitor, L-NNA, and the cGMP antagonist, Rp 8-brom o cGMPs, blunted adenosine-induced pial dilation (8 +/- 1, 14 +/- 1, a nd 20 +/- 3 vs. 3 +/- 1, 5 +/- 1, and 8 +/- 3% for 10(-8), 10(-6), and 10(-4) M adenosine before and after L-NNA, respectively). Adenosine d ilation was also blunted by glibenclamide, a K-ATP antagonist (9 +/- 2 , 14 +/- 3, 21 +/- 4 vs. 4 +/- 1, 8 +/- 2, and 11 +/- 2% for 10(-8), 1 0(-6), and 10(-4) M adenosine before and after glibenclamide, respecti vely). Finally, it was also observed that adenosine-induced dilation w as associated with increased CSF cAMP concentration and the cAMP antag onist, Rp 8-bromo cAMPs, blunted adenosine pial dilation. These data s how that adenosine contributes to hypoxic pial dilation. These data al so show that NO, cGMP, cAMP, and activation of K-ATP channels all cont ribute to adenosine induced pial dilation. Finally, these data suggest that adenosine contributes to hypoxia-induced pial artery dilation vi a cAMP and activation of K-ATP channels by NO and cGMP.